This invention relates to a novel class of hydroxamic acid and N-formyl hydroxylamine derivatives having antibacterial activity, and to pharmaceutical and veterinary compositions comprising such compounds.
In general, bacterial pathogens are classified as either Gram-positive or Gram-negative. Many antibacterial agents (including antibiotics) are specific against one or other Gram-class of pathogens. Antibacterial agents effective against both Gram-positive and Gram-negative pathogens are therefore generally regarded as having broad spectrum activity.
Many classes of antibacterial agents are known, including the penicillins and cephalosporins, tetracyclines, sulfonamides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol. The fundamental mechanisms of action of these antibacterial classes vary.
Bacterial resistance to many known antibacterials is a growing problem. Accordingly there is a continuing need in the art for alternative antibacterial agents, especially those which have mechanisms of action fundamentally different from the known classes.
Amongst the Gram-positive pathogens, such as Staphylococci, Streptococci, Mycobacteria and Enterococci, resistant strains have evolved/arisen which makes them particularly difficult to eradicate. Examples of such strains are methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant coagulase negative Staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium. 
Pathogenic bacteria are often resistant to the aminoglycoside, xcexc-lactam (penicillins and cephalosporins), and chloramphenicol types of antibiotic. This resistance involves the enzymatic inactivation of the antibiotic by hydrolysis or by formation of inactive derivatives. The xcex2-lactam (penicillin and cephalosporin) family of antibiotics are characterised by the presence of a xcex2-lactam ring structure. Resistance to this family of antibiotics in clinical isolates is most commonly due to the production of a xe2x80x9cpenicillinasexe2x80x9d (xcex2-lactamase) enzyme by the resistant bacterium which hydrolyses the xcex2-lactam ring thus eliminating its antibacterial activity.
Recently there has been an emergence of vancomycin-resistant strains of enterococci (Woodford N. 1998 Glycopeptide-resistant enterococci: a decade of experience. Journal of Medical Microbiology. 47(10):849-62). Vancomycin-resistant enterococci are particularly hazardous in that they are frequent causes of hospital based infections and are inherently resistant to most antibiotics. Vancomycin works by binding to the terminal D-Ala-D-Ala residues of the cell wall peptidioglycan precursor. The high-level resistance to vancomycin is known as VanA and is conferred by a genes located on a transposable element which alter the terminal residues to D-Ala-D-lac thus reducing the affinity for vancomycin.
In view of the rapid emergence of multidrug-resistant bacteria, the development of antibacterial agents with novel modes of action that are effective against the growing number of resistant bacteria, particularly the vancomycin resistant enterococci and xcex2-lactam antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus, is of utmost importance.
This invention is based on the finding that certain hydroxamic acid and N-formyl hydroxylamine derivatives have antibacterial activity, and makes available a new class of antibacterial agents. The inventors have found that the compounds with which this invention is concerned are antibacterial with respect to a range of Gram-positive and Gram-negative organisms.
Although it may be of interest to establish the mechanism of action of the compounds with which the invention is concerned, it is their ability to inhibit bacterial growth that makes them useful. However, it is presently believed that their antibacterial activity is due, at least in part, to intracellular inhibition of bacterial polypeptide deformylase (PDF; EC 3.5.1.31).
All ribosome-mediated synthesis of proteins starts with a methionine residue. In prokaryotes the methionyl moiety carried by the initiator tRNA is N-formylated prior to its incorporation into a polypeptide. Consequently, N-formylmethionine is always present at the N-terminus of a nascent bacterial polypeptide. However, most mature proteins do not retain the N-formyl group or the terminal methionine residue. Deformylation is required prior to methionine removal, since methionine aminopeptidase does not recognise peptides with an N-terminal formylmethionine residue (Solbiati et al., J. Mol. Biol. 290:607-614, 1999). Deformylation is, therefore, a crucial step in bacterial protein biosynthesis and the enzyme responsible, PDF, is essential for normal bacterial growth. Although the gene encoding PDF (def) is present in all pathogenic bacteria for which sequences are known (Meinnel et al., J. Mol. Biol, 266:939-49, 1997), it has no eukaryotic counterpart, making it an attractive target for antibacterial chemotherapy.
The isolation and characterisation of PDF has been facilitated by an understanding of the importance of the metal ion in the active site (Groche et al., Biophys. Biochem. Res. Commun., 246:324-6, 1998). The Fe2+ form is highly active in vivo but is unstable when isolated due to oxidative degradation (Rajagopalan et al., J. Biol. Chem. 273:22305-10, 1998). The Ni2+ form of the enzyme has specific activity comparable with the ferrous enzyme but is oxygen-insensitive (Ragusa et al., J. Mol. Biol. 1998, 280:515-23, 1998). The Zn2+ enzyme is also stable but is almost devoid of catalytic activity (Rajagopalan et al., J. Am. Chem. Soc. 119:12418-12419, 1997).
Several X-ray crystal structures and NMR structures of E. coli PDF, with or without bound inhibitors, have been published (Chan et al., Biochemistry 36:13904-9, 1997; Becker et al., Nature Struct. Boil. 5:1053-8, 1998; Becker et al., J. Biol. Chem. 273:11413-6, 1998; Hao et al., Biochemistry, 38:4712-9, 1999; Dardel et al., J. Mol. Biol. 280:501-13, 1998; O""Connell et al., J. Biomol. NMR, 13:311-24, 1999), indicating similarities in active site geometry to metalloproteinases such as thermolysin and the metzincins.
Recently the substrate specificity of PDF has been extensively studied (Ragusa et al., J. Mol. Biol. 289:1445-57, 1999; Hu et al., Biochemistry 38:643-50, 1999; Meinnel et al., Biochemistry, 38:4287-95, 1999). These authors conclude that an unbranched hydrophobic chain is preferred at P1xe2x80x2, while a wide variety of P2xe2x80x2 substituents are acceptable and an aromatic substituent may be advantageous at the P3xe2x80x2 position. There have also been reports that small peptidic compounds containing an H-phosphonate (Hu et al., Bioorg. Med. Chem. Lett., 8:2479-82, 1998) or thiol (Meinnet et al., Biochemistry, 38:4287-95, 1999) metal binding group are micromolar inhibitors of PDF. Peptide aldehydes such as calpeptin (N-Cbz-Leu-norteucinal) have also been shown to inhibit PDF (Durand et al., Arch. Biochem. Biophys., 367:297-302, 1999). However, the identity of the metal binding group and its spacing from the rest of the molecule (xe2x80x9crecognition fragmentxe2x80x9d) has not been studied extensively. Furthermore, non-peptidic PDF inhibitors, which may be desirable from the point of view of bacterial cell wall permeability or oral bioavailability in the host species, have not been identified.
Recently it has been reported that PDF is present in eukaryotic parasites such as Plasmodium falciparum (Ferreira et al, Parasitology Today, vol 16, no. 4, 2000). Those authors also found evidence for the presence of PDF in other parasites of humans, such as the kinetoplastid protozoan parasites Trypanosoma brucei and Leishmania major. Based on these findings, it is anticipated that the compounds with which this invention is concerned have antiprotozoal activity, and are useful in the treatment of malaria and other protozoal diseases.
Certain N-formyl hydroxylamine derivatives have previously been claimed in the patent publications listed below, although very few examples of such compounds have been specifically made and described:
The pharmaceutical utility ascribed to the N-formyl hydroxylamine derivatives in those publications is the ability to inhibit matrix metalloproteinases (MMPs) and in some cases release of tumour necrosis factor (TNF), and hence the treatment of diseases or conditions mediated by those enzymes, such as cancer and rheumatoid arthritis. That prior art does not disclose or imply that N-formyl hydroxylamine derivatives have antibacterial activity.
In addition to these, U.S. Pat. No. 4,738,803 (Roques et al.) also discloses N-formyl hydroxylamine derivatives, however, these compounds are disclosed as enkephalinase inhibitors and are proposed for use as antidepressants and hypotensive agents. Also, WO 97/38705 (Bristol-Myers Squibb) discloses certain N-formyl hydroxylamine derivatives as enkephalinase and angiotensin converting enzyme inhibitors. This prior art does not disclose or imply that N-formyl hydroxyiamine derivatives have antibacterial activity either.
Our copending International patent applications nos. WO 99/39704 and WO 99/59568 disclose that certain N-formyl hydroxylamine and hydroxamic acid derivatives have antibacterial activity. One class of compounds disclosed therein as having such activity has general formula (IA): 
Wherein X represents an N-formylhydroxylamino group (xe2x80x94N(OH)CHO) or a hydroxamic acid group (xe2x80x94CONHOH), and the various xe2x80x9cRxe2x80x9d substituents are as specified in the documents. The compounds useful in accordance with the present invention differ in structure from those of WO 99/39704 and WO 99/59568 principally in that the amido radical R6R5NCOxe2x80x94 is replaced by a ketone radical.
Very many hydroxamic acid derivatives are known. Many have been disclosed as having matrix metalloproteinase (MMP) inhibitory activity, and thus to be potentially useful for the treatment of diseases mediated by MMPs, for example cancer, arthritides, and contitions involving tissue remodeling such as wound healing, and restenosis. However, very few such known hydroxamic acid derivatives have the ketone moiety which characterises the compounds useful according to the present invention. One publication which does, however, is WO 98/30541 (Abbott).
According to the first aspect of the present invention there is provided the use of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof in the preparation of a composition for treatment of bacterial or protozoal infections in humans and non-human mammals: 
wherein:
Z represents a radical of formula xe2x80x94N(OH)CH(xe2x95x90O) or formula xe2x80x94C(xe2x95x90O)NH(OH);
R1 represents hydrogen, methyl or trifluoromethyl, or, except when Z is a radical of formula xe2x80x94N(OH)CH(xe2x95x90O), a hydroxy or amino group;
R2 represents a group R10xe2x80x94(X)nxe2x80x94(ALK)mxe2x80x94 wherein
R10 represents hydrogen, or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, aryl, or heterocyclyl group, any of which may be unsubstituted or substituted by (C1-6)alkyl, (C1-6)alkoxy, hydroxy, mercapto, (C1-6)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, oxo, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94COORA, xe2x80x94NHCORA, xe2x80x94CONHRA, xe2x80x94NHRA, NRARB, or xe2x80x94CONRARB wherein RA and RB are independently a (C1-6)alkyl group and
ALK represents a straight or branched divalent C1-6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radical, and may be interrupted by one or more non-adjacent xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 linkages,
X represents xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and
m and n are independently 0 or 1;
R3 represents the side chain of a natural or non-natural alpha amino acid; and
R4 represents a radical R5xe2x80x94(ALK)pxe2x80x94 wherein ALK is as defined in relation to R2, p is 0 or 1, and R5 represents hydrogen, or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, aryl, or heterocyclyl group any of which
(i) may be substituted by a group selected from (C1-6)alkyl, phenyl, benzyl, (C1-6)alkoxy, phenoxy, hydroxy, mercapto, (C1-6)alkylthio, amino, halo, trifluoromethyl, cyano, nitro, oxo, xe2x80x94COOH, xe2x80x94SO2H, xe2x80x94CONH2, xe2x80x94SO2NH2, xe2x80x94CORA, xe2x80x94SORA, xe2x80x94SO2RA, xe2x80x94SO2RA, xe2x80x94COORA, xe2x80x94CONHRA, xe2x80x94SO2NHRA, xe2x80x94NHCORA, xe2x80x94NHSO2RA, and xe2x80x94NHRA, wherein RA is
(C1-6)alkyl, cycloalkyl, phenyl, 2-, 3- or 4-pyridyl, N- or 2-, 3- or 4-piperidyl, N- or 2- or 3-piperazyl group; or
(ii) may be substituted by xe2x80x94NRARB, xe2x80x94CONRARB or xe2x80x94SO2NRARB, wherein RA and RB are independently
(C1-C6)alkyl, cycloalkyl, phenyl, 2-, 3- or 4-pyridyl, N- or 2-, 3- or 4-piperidyl, N- or 2- or 3-piperazyl group,
or when taken together with the N atom to which they are attached RA and RB form a 5 to 7 membered aromatic or non-aromatic ring, which ring (a) may contain additional heteroatoms selected from N, O and S, and in which any S atom may be oxidised as a sulphonyl or sulphoxide, and (b) may be substituted on a ring carbon or heteroatom by one or more of the substituents listed under (i) above.
In another aspect, the invention provides a method for the treatment of bacterial or protozoal infections in humans and non-human mammals, which comprises administering to a subject suffering such infection an antibacterially effective dose of a compound of formula (I) as defined above.
In a further aspect of the invention there is provided a method for the treatment of bacterial contamination by applying an antibacterially effective amount of a compound of formula (I) as defined above to the site of contamination.
The compounds of formula (I) as defined above may be used as component(s) of antibacterial cleaning or disinfecting materials.
Compounds of formula (I) above wherein Z is a radical of formula xe2x80x94N(OH)CH(xe2x95x90O), are believed to be novel. Accordingly, in another aspect, the invention provides a compound of formula (I) wherein Z is a radical of formula xe2x80x94N(OH)CH(xe2x95x90O), or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof.
On the hypothesis that the compounds (I) act by inhibition of intracellular PDF, the most potent antibacterial effect may be achieved by using compounds which efficiently pass through the bacterial cell wall. Thus, compounds which are highly active as inhibitors of PDF in vitro and which penetrate bacterial cells are preferred for use in accordance with the invention. It is to be expected that the antibacterial potency of compounds which are potent inhibitors of the PDF enzyme in vitro, but are poorly cell penetrant, may be improved by their use in the form of a prodrug, ie a structurally modified analogue which is converted to the parent molecule of formula (I), for example by enzymic action, after it has passed through the bacterial cell wall. The same is true in the case of protozoa.
As used herein the term xe2x80x9c(C1-C6)alkylxe2x80x9d means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
As used herein the term xe2x80x9cdivalent (C1-C6)alkylene radicalxe2x80x9d means a saturated hydrocarbon chain having from 1 to 6 carbon atoms and two unsatisfied valencies.
As used herein the term xe2x80x9c(C2-C6)alkenylxe2x80x9d means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. The term includes, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
As used herein the term xe2x80x9cdivalent (C2-C6)alkenylene radicalxe2x80x9d means a hydrocarbon chain having from 2 to 6 carbon atoms, at least one double bond, and two unsatisfied valencies.
As used herein the term xe2x80x9cC2-C6 alkynylxe2x80x9d refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
As used herein the term xe2x80x9cdivalent (C2-C6)alkynylene radicalxe2x80x9d means a hydrocarbon chain having from 2 to 6 carbon atoms, at least one triple bond, and two unsatisfied valencies.
As used herein the term xe2x80x9ccycloalkylxe2x80x9d means a saturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein the term xe2x80x9ccycloalkenylxe2x80x9d means an unsaturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. In the case of cycloalkenyl rings of from 5-8 carbon atoms, the ring may contain more than one double bond.
As used herein the term xe2x80x9carylxe2x80x9d refers to a mono-, bi- or tri-cyclic carbocyclic aromatic group, and to groups consisting of two covalently linked monocyclic carbocyclic aromatic groups. Illustrative of such groups are phenyl, biphenyl and napthyl.
As used herein the unqualified term xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d includes xe2x80x9cheteroarylxe2x80x9d as defined below, and in particular means a 5-8 membered aromatic or non-aromatic heterocyclic ring containing one or more heteroatoms selected from S, N and O, and optionally fused to a benzyl or second heterocyclic ring, and the term includes, for example, pyrrolyl, furyl, thienyl, piperidinyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, thiazepinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, and benzimidazolyl rings.
As used herein the term xe2x80x9cheteroarylxe2x80x9d refers to a 5- or 6-membered aromatic ring containing one or more heteroatoms, and optionally fused to a benzyl or pyridyl ring; and to groups consisting of two covalently linked 5- or 6-membered aromatic rings each containing one or more heteroatoms; and to groups consisting of a monocyclic carbocyclic aromatic group covalently linked to a 5- or 6-membered aromatic rings containing one or more heteroatoms. Illustrative of such groups are thienyl, furyl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, 4-([1,2,3]-thiadiazoly-4-yl)phenyl and 5-isoxazol-3-ylthienyl.
As used herein the unqualified term xe2x80x9ccarbocyclylxe2x80x9d or xe2x80x9ccarbocyclicxe2x80x9d refers to a 5-8 membered ring whose ring atoms are all carbon.
Unless otherwise specified in the context in which it occurs, the term xe2x80x9csubstitutedxe2x80x9d as applied to any moiety herein means substituted with up to four substituents, each of which independently may be (C1-C6)alkyl, phenyl, benzyl, (C1-6)alkoxy, phenoxy, hydroxy, mercapto, (C1-6)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, oxo, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94CORA, xe2x80x94COORA, xe2x80x94NHCORA, xe2x80x94CONHRA, xe2x80x94NHRA, xe2x80x94NRARB, or xe2x80x94CONRARB wherein RA and RB are independently a (C1-6)alkyl group. In the case where xe2x80x9csubstitutedxe2x80x9d means substituted by benzyl, the phenyl ring thereof may itself be substituted with any of the foregoing, except phenyl or benzyl.
As used herein the terms xe2x80x9cside chain of a natural alpha-amino acidxe2x80x9d and xe2x80x9cside chain of a non-natural alpha-amino acidxe2x80x9d mean the group Rx in respectively a natural and non-natural amino acid of formula NH2xe2x80x94CH(Rx)xe2x80x94COOH.
Examples of side chains of natural alpha amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, histidine, 5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, xcex1-aminoadipic acid, xcex1-amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserine, xcex1-methylserine, ornithine, pipecolic acid, and thyroxine.
In natural alpha-amino acid side chains which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl, or indolyl groups as in arginine, lysine, glutamic acid, aspartic acid, tryptophan, histidine, serine, threonine, tyrosine, and cysteine, such functional substituents may optionally be protected.
Likewise, in the side chains of non-natural alpha amino acids which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl, or indolyl groups, such functional substituents may optionally be protected.
The term xe2x80x9cprotectedxe2x80x9d when used in relation to a functional substituent in a side chain of a natural or non-natural alpha-amino acid means a derivative of such a substituent which is substantially non-functional. The widely used handbook by T. W. Greene and P. G. Wuts xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d Second Edition, Wiley, New York, 1991 reviews the subject. For example, carboxyl groups may be esterified (for example as a C1-6 alkyl ester), amino groups may be converted to amides (for example as a NHCOC1-6 alkyl amide) or carbamates (for example as an NHC(xe2x95x90O)OC1-6 alkyl or NHC(xe2x95x90O)OCH2Ph carbamate), hydroxyl groups may be converted to ethers (for example an OC1-6 alkyl or a O(C1-6 alkyl)phenyl ether) or esters (for example a OC(xe2x95x90O)C1-C6 alkyl ester) and thiol groups may be converted to thioethers (for example a tert-butyl or benzyl thioether) or thioesters (for example a SC(xe2x95x90O)C1-6 alkyl thioester).
There are at least two actual or potential chiral centres in the compounds according to the invention because of the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to a number of diastereoisomers with R or S stereochemistry at each chiral centre. The invention includes all such diastereoisomers and mixtures thereof. Currently, the preferred stereoconfiguration of the carbon atom carrying the R2 group is R; that of the carbon atom carrying the R1 group (when asymmetric) is R; and that of the carbon atom carrying the R3 group (when asymmetric) is S
In the compounds of formula (I) as defined above:
R1 is hydrogen, methyl, or trifuoromethyl. Hydrogen is currently preferred.
R2 may be, for example:
optionally substituted C1-C8 alkyl, C3-C6 alkenyl, C3-C6 alkynyl or cycloalkyl;
phenyl(C1-6 alkyl)-, phenyl(C3-C6 alkenyl)- or phenyl(C3-C6 alkynyl)-optionally substituted in the phenyl ring;
cycloalkyl(C1-6 alkyl)-, cycloalkyl(C3-C6 alkenyl)- or cycloalkyl(C3-C6 alkynyl)-optionally substituted in the cycloalkyl ring;
heterocyclyl(C1-C6 alkyl)-, heterocyclyl(C3-C6 alkenyl)- or heterocyclyl(C3-C6 alkynyl)-optionally substituted in the heterocyclyl ring; or
CH3(CH2)pO(CH2)qxe2x80x94 or CH3(CH2)pS(CH2)qxe2x80x94, wherein p is 0, 1, 2 or 3 and q is 1, 2 or 3.
Specific examples of R2 groups include
methyl, ethyl, n- and iso-propyl, n- and iso-butyl, n-pentyl, iso-pentyl 3-methyl-but-1-yl, n-hexyl, n-heptyl, n-acetyl, n-octyl, methylsulfanylethyl, ethylsulfanylmethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-ethoxymethyl, 3-hydroxypropyl, allyl, 3-phenylprop-3-en-1-yl, prop-2-yn-1-yl, 3-phenylprop-2-yn-1-yl, 3-(2-chlorophenyl)prop-2-yn-1-yl, but-2-yn-1-yl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, furan-2-ylmethyl, furan-3-methyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylmethyl, piperidinylmethyl, phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl, and 4-methoxybenzyl.
Presently preferred groups at R2 are n-propyl, n-butyl, n-pentyl, and cyclopentylmethyl.
R3 may be, for example
the characterising group of a natural a amino acid, for example benzyl, or 4-methoxyphenylmethyl, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated; or
a group -[Alk]nR9 where Alk is a (C1-6)alkylene or (C2-C6)alkenylene group optionally interrupted by one or more xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R12)xe2x80x94 groups [where R12 is a hydrogen atom or a (C1-6)alkyl group], n is 0 or 1, and R9 is hydrogen or an optionally substituted phenyl, aryl, heterocyclyl, cycloalkyl or cycloalkenyl group or (only when n is 1) R9 may additionally be hydroxy, mercapto, (C1-6)alkylthio, amino, halo, trifluoromethyl, nitro, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94COORA, xe2x80x94NHCORA, xe2x80x94CONHRA, xe2x80x94NHRA, xe2x80x94NRARB, or xe2x80x94CONRARB wherein RA and RB are independently a (C1-C6)alkyl group; or
CONH2, xe2x80x94COORA, xe2x80x94NHCORA, xe2x80x94CONHRA, xe2x80x94NHRA, xe2x80x94NRARB, or xe2x80x94CONRARB wherein RA and RB are independently a (C1-6)alkyl group; or
a benzyl group substituted in the phenyl ring by a group of formula xe2x80x94OCH2COR3 where R8 is hydroxyl, amino, (C1-6)alkoxy, phenyl(C1-6)alkoxy, (C1-6)alkylamino, di((C1-6)alkyl)amino, phenyl(C1-C6)alkylamino; or
a heterocyclic(C1-6)alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C1-6)alkoxy, cyano, (C1-6)alkanoyl, trifluoromethyl (C1-6)alkyl, hydroxy, formyl, amino, (C1-6)alkylamino, di-(C1-6)alkylamino, mercapto, (C1-6)alkylthio, hydroxy(C1-6)alkyl, mercapto(C1-6)alkyl or (C1-C6)alkylphenylmethyl; or
a group xe2x80x94CRaRbRc in which:
each of Ra, Rb and Rc is independently hydrogen, (C1-6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-C6)alkyl, (C3-C8)cycloalkyl; or
Rc is hydrogen and Ra and Rb are independently phenyl or heteroaryl such as pyridyl; or
Rc is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, phenyl(C1-C6)alkyl, or (C3-C8)cycloalkyl, and Ra and Rb together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; or
Ra, Rb and Rc together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or
Ra and Rb are each independently (C1-6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-6)alkyl, or a group as defined for Rc below other hydrogen, xe2x80x94OH, xe2x80x94SH, halogen, xe2x80x94CN, xe2x80x94CO2H, (C1-4)perfluoroalkyl, xe2x80x94CH2OH, xe2x80x94CO2(C1-6)alkyl, xe2x80x94O(C1-6)alkyl, xe2x80x94O(C2-C6)alkenyl, xe2x80x94S(C1-C6)alkyl, xe2x80x94SO(C1-C6)alkyl, xe2x80x94SO2(C1-6)alkyl, xe2x80x94S(C2-C6)alkenyl, xe2x80x94SO(C2-C6)alkenyl, xe2x80x94SO2(C2-C6)alkenyl or a group xe2x80x94Qxe2x80x94W wherein Q represents a bond or xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94 and W represents a phenyl, phenylalkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkylalkyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2(C1-C6)alkyl, xe2x80x94CONH2, xe2x80x94CONH(C1-C6)alkyl, xe2x80x94CONH(C1-C6alkyl)2, xe2x80x94CHO, xe2x80x94CH2OH, (C1-C4)perfluoroalkyl, xe2x80x94O(C1-C6)alkyl, xe2x80x94S(C1-C6)alkyl, xe2x80x94SO(C1-C6)alkyl, xe2x80x94SO2(C1-6)alkyl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NH(C1-C6)alkyl, xe2x80x94N((C1-C6)alkyl)2, xe2x80x94NHCO(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, phenyl or benzyl.
Examples of particular R3 groups include methyl, ethyl, benzyl, 4-chlorobenzyl, 4-hydroxybenzyl, phenyl, cyclohexyl, cyclohexylmethyl, pyridin-3-ylmethyl, tert-butoxymethyl, naphthylmethyl, iso-butyl, sec-butyl, tert-butyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, 1-mercapto-1-methylethyl, 1-methoxy-1-methylethyl, 1-hydroxy-1-methylethyl, 1-fluoro-1-methylethyl, hydroxymethyl, 2-hydroxethyl, 2-carboxyethyl, 2-methylcarbamoylethyl, 2-carbamoylethyl, and 4-aminobutyl. Presently preferred R3 groups include tert-butyl.
R4 may be, for example
optionally substituted C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or cycloalkyl;
optionally substituted phenyl, biphenyl or naphthyl;
optionally substituted piperidinyl, cyclohexyl, cyclopentyl, oxazolyl, thiazepinyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, optionally substituted piperidinyl, cyclohexyl, cyclopentyl, oxazolyl, thiazepinyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, thienyl, furanyl, pyrrolyl, imidazolyl, benzofuranyl, benzothienyl, benzimidazolyl, thiazolyl, benzothiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, or triazinyl.
phenyl(C1-C6 alkyl)-, phenyl(C2-C6 alkenyl)- or phenyl(C2-C6 alkynyl)-optionally substituted in the phenyl ring;
cycloalkyl(C1-C6 alkyl)-, cycloalkyl(C2-C6 alkenyl)- or cycloalkyl(C2-C6 alkynyl)-optionally substituted in the cycloalkyl ring;
heterocyclyl(C1-C6 alkyl)-, heterocyclyl(C2-C6 alkenyl)- or heterocyclyl(C2-C6 alkynyl)-optionally substituted in the heterocyclyl ring.
Specific examples of R4 groups include
Methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-phenylcycloprop-1-yl, benzyl, biphenyl-2-yl, biphenyl-3-yl, biphenyl-l-4-yl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 2-N,N-dimethylaminophenyl, 3-N,N-dimethylaminophenyl, 4-N,N-dimethylaminophenyl, 2-methanesulfonamidophenyl, 3-methanesulfonamidophenyl, 4-methanesulfonamidophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 2-thiophenolyl, 3-thiophenolyl, 4-thiophenolyl, 2-thioanisolyl, 3-thioanisolyl, 4-thioanisolyl, 1-naphthyl, 2-naphthyl, furan-2-yl, thien-2-yl, pyrrol-2-yl, 1-methylpyrrol-2-yl, imidazol-2-yl, 1-methylimidazol-2-yl, thiazol-2-yl, 5-phenylpyrrol-2-yl, 5-phenylfuran-2-yl, 5-phenylthien-2-yl, benzothiazol-2-yl, 1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxides of pyridin-2-yl pyridin-3-yl and pyridin-4-yl, indol-2-yl, indol-3-yl, 1-methylindol-2-yl, 1-methylindol-3-yl, benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, pyrazin-2-yl, 1,2-pyridazin-3-yl, 1,3-pyrimidin-2-yl, benzo[b]thien-2-yl, benzo[b]thien-3-yl, benzo[b]furan-2-yl, benzo[b]furan-3-yl, isoxazol-5-yl, quinolin-2-yl, quinolin-3-yl, isoquinolin-2-yl, isoquinolin-3-yl, 2-oxo-2-phenylethyl, diphenylmethyl, 4-N-methylaminophenyl, 4-N,N-dimethylcarboxamidophenyl, and 4-carboxyphenyl. R4 may be a phenyl group which is substituted , for example in the 4-position, by one of the following: 
In the compounds of formula (I) as defined above wherein Z is a radical of formula xe2x80x94C(xe2x95x90O)NH(OH) the radicals R1, R2, R3, R4 may be any of those discussed above in relation to compounds (I) wherein Z is a radical of formula xe2x80x94N(OH)CH(xe2x95x90O). However, in addition, R1 may be, for example, a hydroxy, methoxy, ethoxy, n-propyloxy, allyloxy, amino, methylamino, dimethylamino, ethylamino, or diethylamino group.
Specific examples of compounds of the invention include those disclosed in the Examples herein.
Compounds of the invention wherein Z is a radical of formula xe2x80x94N(OH)CH(xe2x95x90O) may be prepared by N-formylation of a compound of formula (II) 
wherein xe2x80x94OP represents a protected hydroxy group, and R1, R2, R3 and R4 are as defined in relation to formula (I) except that any reactive groups present therein which are reactive with the formylation reagent are protected, and then converting xe2x80x94OP to a hydroxy group and removing any protecting groups present in R1, R2, R3 or R4. Formylacetic anhydride is a convenient formylating agent for this reaction.
Compounds of formula (II) may be synthesised from easily accessible or commercially available starting materials, or by standard synthetic routes analogous to those shown in Schemes 1 and 2 below.
Hydroxamate compounds of formula (I) for use in accordance with the invention may be prepared by reacting the parent compound wherein Z is a carboxylic acid group with hydroxylamine or an N- and/or O-protected hydroxylamine, and thereafter removing any O- or N-protecting groups.
Antibacterial or antiprotozoal compositions with which the invention is concerned may be prepared for administration by any route consistent with the pharmacokinetic properties of the active ingredient(s).
Orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
For topical application to the skin, the active ingredient(s) may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
The active ingredient(s) may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. Intra-venous infusion is another route of administration for the compounds used in accordance with the invention.
Safe and effective dosages for different classes of patient and for different disease states will be determined by clinical trial as is required in the art. It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The following example illustrate embodiments of the invention.
The following abbreviations have been used throughout:
1H and 13C NMR spectra were recorded using a Bruker AC 250E spectrometer at 250.1 and 62.9 MHz, respectively. Mass spectra were obtained using a Perkin Elmer Sciex API 165 spectrometer using both positive and negative ion modes.
Where MIC values are quoted for the compounds of the examples, those results were obtained by the method described in the Biological Example.